1-methyl-pregnanes



May 26j,` 1964 B. CAMERINO ET AL l-METHYL-PREGNANES F'iled'Augf. 9",19.61

COCHS ACO- Hydrcgenation Pd C COCH3 ACO ACO- CHOHI Seleci ive,

acetylation I C-LOAC ACO- Oxidation CHOAC AcO- XX G r'ngnard 5-Sheets-Sheet 1 HO- Ia,Ib

com3

ACO CH3 HO- m Hydmgenatxon Pd/C coen-43 ACO H3 0= XXI Inventors @rah ooaeneno /Poberl'z au May 26, 1964 B. CAMERINO ETAL 3,134,793

l-METHYL-PREGNANES Filed Aug. 9, 1961 5 Sheets-sheet 2 HO- Ia,Ib

Seiectve Selechve acetylation oxdaton oH o ACO- ma. Ha'

Oxdatin Acetylaton Grignani ACO- ma, E b

lclrgnard Ho CH3 "l l HO- Va,

May 25, 1954 B. CAMERINO ETAL 3,134,793

Filed Aug. 9, 1961 5 Sheets-Sheet 5 /Z/fw, Tk@ Attorneys May 26, 1964 B.CAMERINO ETA.. 3,134,793

l-METHYL-PREGNANES Filed Aug. 9, 1961 5 Sheets-Sheet 5 CH2 l CHz jSaponpcatl'on AcO- XXX a Ho' XXXI 0.

m b Hydrogenaten Pa.

Jaa?? ober?" 7 Attorneys United States Patent O 3,134,793l-METHYL-PREGNANES Bmno Camerino and Roberto Sciaky, both of Via Turati18, Milan, Italy, and Jean Robert, 28 Ave. Pasteur, Gentilly, Seine,France Filed Aug. 9, 1961, Ser. No. 130,388 Claims priority, applicationGreat Britain Oct. 28, 1959 4 Claims. (Cl. 260-397.4)

This invention relates to new steroid compounds, to new processes forthe preparation of steroids and to cornpositions containing the said newcompounds. More particularly, it concerns certain new and usefull-methylgenins, l-methylene genins and l-methyl-pregnane derivatives anda new and advantageous process for the preparation of l-methyl-geninsand l-methyl-pregnane derivatives in general.

Some l-methyl steroids are already known, but they either contain anaromatic nucleus (the A or B ring) or are derived from the 19-nor seriesand their prepara- 2 tion in both cases necessitates the transpositionof the methyl group from the 10- to the l-position, or they 3,134,793Patented May 26,' 1 964 ICC Soc. 78, 2477 (1956)] andl-rnethyl-19-nor-progesterone and its derivatives [Djerassi et coll., I.Am. Chem. Soc. 78, 2479 (1956)], may be obtained by Birchs reduction ofthe corresponding l-methyl-Al1353alkoxyestra trienes; and1-methyl-Al-S-keto-dehydrosteroids, may be prepared by the action ofdiazornethane on A1-3-keto-dehydrosteroids, followed by pyrolysis of theadduct [as described in German Patent 1,023,764].

The present invention provides a method of introducing a methyl groupinto the l-position of steroids possessing a double bond in theS-position. The presence of this A5 bond is fundamental, since it caneasily be caused to migrate to the 4-position and the majority ofphysiologically active steroids, such as progestationals, androgens, andanti-inammatories are A4 compounds.

According toa first feature of the invention, there are provided newl-methyl-steroids and lemethylene steroids which are the l-methyl geniusof the following general Auslegeschrift No.

0 Formulae 1, 2 and 3, the l-rnethyl-pregnane derivatives of thefollowing general Formula 4 and the l-methylenegenins of the followinggeneral Formulae 5 and 6:

possess no double bond in the 4- or 5position. For

instance, the 1-methyl-AG-dehydro-estrogens (described in United StatesPatent No. 2,671,092) may be prepared by rearrangement ofA1A--keto-dehydrosteroids by treating the latter with a catalyst capableof producing the dienone-phenol rearrangement; 1-methyl-l9nortestosterone and its derivatives [Ringold et coll.,'l. Ain. Chem.

wherein the various symbols used have the following meanings:

(It will be noted that there is an additional hydrogen atom present inthe 11S-position, which has not been mentioned in the aforesaid valuesof Z.)

:O or (-H)-OH or (-H)-OCOCH3 R"=an acyl group containing up to 9 carbonatoms derived from a cyclic or non-cyclic aliphatic carboxylic acid orfrom an aromatic carboxylic acid. (If R" is derived from a cyclicaliphatic or aromatic acid, the group -CO- which is included may beattached directly to the nucleus or may occur in a side chain and R mayrepre- Utilising the nomenclature of M. E. Wall and S. Serota [1. Am.Chem. Soc. 79, 6481 (1957)], the spiroketal chain in general formulae 1and 5 has the configuration 20a, 22,8, 25D, as in the case of diosgenin,and the spiroketal chain in general Formula 3 has the configuration 20a,2218, 25L, as in the case of yamogenin. In general Formulae 2 and 6 theethylenic spiroketal chain is the same as in neoruscogenin [1. Robert,R. Vaupre and G. Poiget, C. R. Acad. Sc. 250, 3187 (1960)]. In thegeneral Formulae 1, 2 and 3, a double bond always exists in the 4,5- or5,6-position and may exist in the 1,2-position. In general Formula 4 adouble bond is always present in the 4,5- or 5,6-position and may existin the 1,2-position and/or the 16,17-position.

The preferred compounds of the invention are the A4, A5, A'16 and A1Aderivatives, and more especially 1- methyl-1-hydroxy-diosgenin,l-methyl-1hydroxy-A25(27) dehydrodiosgenin, l-methyl-diosgenin,l-methyl-yamoselective l C O Y CH3 wherein Y has the significancepreviously assigned to it and Z represents a hydrgoen atom or a hydroxyor acetoxy group, are physiologically active compounds which exhibitprogestative properties and may be employed in the treatment of thefollowing conditions: primary amenorrhea, functional dysmenorrhea,hypo-oligo-menorrhea,

sterility, menorrhagia, habitiual abortion, threatened abor- 5 tion andovulatory disorders. This progestative activity is particularlypronounced in the case of 1-methyl-17aacetoxy-progesterone.

According to a further feature of the invention there is provided amethod for the preparation of a l-methyll-hydroxy-steroid whichcomprises subjecting a 1,3-dihydroxy-steroid to oxidation in thel-position, and reacting the resultant 1ketosteroid with a metallicderivative of methane.

In a specific application of the foregoing general method the formationof 1-methyl-l-hydroxy-genins, such as 1-methy1 1 hydroxy-diosgenin orl-methyl-l-hydroxy- A25(27)-dehydrodiosgenin, is effected by the actionof a metallic lderivative of methane (also referred to herein as aGrignard reagent), such as CH3Mgl, CHaMgBr or CHaLi, in an appropriatesolvent, either:

(a) On 1-keto-genins 'having a free hydroxyl group in the 3-position,such as l-keto-diosgenin or 1keto-A25(27) dchydrodiosgenin, which areprepared by selective oxidation in the 1-position of1,3-dihydroxy-genins, such as ruscogenin and neoruscogenin (this isshown as route (1), (2) in the flow-.sheet set out below), or

(b) On 1ketogenins having an acetoxy group in the 3-position.

The 3-acetoxy-1-keto-genins are obtained by selective acetylation of1,3-dihydroxy-genins followed by oxidation in the 1position or byselective oxidation in the l-position of 1,3-dihydroxy-genins followedby acetylation in t-he 3-position (thesefare shown as routes (3), (4),(5) and (1), (6), (5), respectively, in the following flow sheet).

Rn =acety1 group The steroids of the pregnane series can be obtained bysimilar methods. However, in the case of 20 lieto-compounds, beforeproceeding with either of the above routes (l), (2) or (1), (6), (5) itis necessary to block the 20-keto group, for example by Iforming acyclic acetal, so that it does not react with the Grignard reagent.Further, if the route (3), (4), (5) is used, it is preferable to reducethe ZO-keto group to a secondary alcohol group and then to effect aselective acetylation in the 3- and 20- positions of the 1,3,20-triolobtained before oxidising in the l-position. It is to be noted that, inthe treatment by the above methods of compounds of the pregnane series,a l-methyl-l,3-dihydroxy-20-keto-pregnane derivative is obtained byusing the routes (l), (2) or (1), (6), (5), While a1-methyll,3,20-trihydr0xy-pregnane derivative is obtained by using theroute (3), (4), (5 It is possible to convert the latter type ofderivative to the corresponding ZO-keto derivative.

As starting materials in carrying out the aforesaid process there may beemployed ruscogenin and neoruscogenin which are steroidic sapogennsisolated from Ruscus aculeatus L. [H. Lapin, C. R. Acad. Sc. 244, 3065(1957); Ch. Sannie and H. Lapin, Bull Soc. Chim. 1237 (1957);

l. Robert, R. Vaupre and G. Poiget,-C. R. Acad. Sc., 250, 3187 (196mlAccording to a further feature of the invention thereis provided amethod for the preparation of a l-methylsteroid free from a hydroxylgroup in the l-posi-tion which comprises acetyl-ating in the 3-positiona lmethyll,3 dihydroXy-steroid, dehydrating in the l-position theresultant l-methyl-lhydroxy-3-acetoxy-steroid and hydrogenating thel-methylene-3-acyloxy-steroid thus obtained.

In a specic application of the above general method` CH2 CH3 1n analternative route, for the preparation of the corresponding 3-hydroxycompound, the hydrogenation step is preceded by saponiiica-tion of the1-methylene-3-acetoxy compound. The same series of reactions can becarried out starting from l-methyl-l-hydroXy-steroids of the pregnaneseries to produce 1-methyl-pregnane derivatives.

According to a further feature of the invention there is provided amodification of the method set forth above for the preparation of al-methyl-steroid free from a hydroxyl group in the .l-position wherein,for the preparation of 1-methylA14-3-keto-steroids, the said l-methyl-1,3-dil1ydroxy-steroid is oxidised in the 3-position and Ithe resultant3-keto compound is dehydrated.

IIt Iwill be observed that in the above modification, where the hydroxylgroup in the 3-position is oXid-ised, the dehydration s-tep gives, notthe l-methylene derivative, but the 1-methy1-A1 derivative. And,further, since the dehydration is effected in a strongly acid orstrongly alkaline medium, a transposition of the double bond from the 5-position to the 4position occurs, which permits of directly isolatingeither the l-methyl-Al14-3-keto-genins or the 1-methyl-Al4-3-keto-pregnane derivatives. As an alternative procedure itis possible to isomerise the said 3-'keto compound, by treatment withVan acid or alkali, into the corresponding A4 :derivative prior to thedehydration step. r[These procedures are diagr-ammatically representedas According to a further feature of the invention there is provided asecond modification of the method set forth above for' the preparationof -a l-methyl-steroid free from a hydroxyl group in the l-positionwherein, for the preparation of l-methyl-A1f4-3-keto-steroids, al-methyl-l-acetoxy3hydroxysteroid is oxidised in the 3-position and the3-position and the B-keto compound thus obtained is treated with analkali or acid whereby the elements of an acetic acid molecule areeliminated forming a double bond in the :L2-position.

The series of transformations in the said second modification set forthabove is accompanied by a transposition of the double bond in theA5-posi-tion to the Ai-position and can be diagrammatically representedas follows:

It will be observed that when the 3-keto compound is treated with acid,the product, depending upon the operating conditions, is either a-1-methyl-Al'4-3-keto-steroid or a l-methyl-l-acetoXy-At-3-keto-steroid.

The latter type of compound can be treated with acidr or alkali toproduce a A1 double bond.

The various processes hereinbefore set forth are illustratedschematically in the accompanying drawings. The tive sheets of drawingsplaced together in the following relative positions:

represents either in the case of products having a 20u,22,25D spiroketalchain, and these lare represented by the letter a being placed after theRoman numeral allotted to each compound, or

in the case of products :having the ethylenic spiroketal chain ofneoruseoogenin, and these are represented by 7 the letter b placed afterthe Roman numeral allotted to each compound, or

in the case of products having a 20nt,22,25L spiroketal chain, and theseare represented by the letter c being placed after the Roman numeralallotted to each corri; pound. In the formulae of the drawing, the groupR has the meaning hereinbefore given, and AC represents the acetylgroup.

Referring now to the accompanying drawing, the selective oxidation ofruscogenin (Ia) or of neoruscogenin (Ib) to l-keto-diosgenin (IIa) or1-ketoA25( 27)-dehydrodiosgenin (IIb) can be carried out by thelomdation with pyridine/CrO3 complex of (IIa) or (Ib), dissolved inpyridine, for about 12 to 24 hours at room temperature and withagitation. It is also possible to effect the oxidation of (Ia) or (Ib),dissolved in an appropriate solvent such as acetone, with an aqueoussolution of a mixture of chromic and sulphuric acids and operating at atemperature between 15 and +20 C. n

By reaction of l-ketoadiosgenin (IIa) or l-keto-AWlldehydrodiosgenin(IIb) with a Grignard reagent such as methylmagnesium bromide or iodide,in a solvent such as benzene, ether or tetrahydrofuran, or binarymixtures of these solvents, followed by decomposition with acids or anaqueous solution of ammonium chloride, there is obtained1-methyl-1hydroxydiosgenin (Va) or 1-methyl- 1hydroxyA25 27dehydrodiosgenin (Vb). The same products (Va) and (Vb) can be preparedby acetylation of (IIa) or (IIb), for example by means ot aceticanhydiide in pyridine to obtain the corresponding acetates (IVa) and(IVb), which are thereafter reacted with a Grignard reagent. Thesederivatives (IVa) and (IVb), can also be obtained from (Ia) or (Ib), ofwhich selective acetylation in the 3-position gives the corresponding3acetates (IIIa) and (IIIb). The latter two compounds, dissolved in ariappropriate solvent such as acetone, are oxidised at a temperaturebetween 15 C. and C. with an aqueous solution of a mixture of sulphuricand chromic acids. t

By degradation of l-methyl-l-hydroxy-diosgenin (Va) or of1-metl1yl-1-hydroxy-A25(27)-dehydrodiosgenin (Vb) there is obtainedl-methyl-A5f16pregnadiene1,3-diol-2O- one-l-acetate. `(VI), which can`also be obtained by degradation of the products (XXIXa) and (XXIXb), ofwhich the preparation will hereinafter be described. t

The compound (VI), treated with hydrogen peroxlde and alkali inmethanolic solution, yields the 16a,17c t epoxy derivative (VII), whichby acetylation with pyridine and acetic anhydride may be transformedinto the 1,3-diacetate (IX). This product (IX) can be converted back tocompound (VII) by saponification.l-methyll6a,17a-epoxy-A14-pregnadiene-3,2O-dione (VIII) is synthesised4from the 1,3-dihydroxy-1-acetate derivative (VII) which is oxidised, inan appropriate solvent such as acetone, with an aqueous solution of amixture of chromic and sulphuric acids at 15 to +20 C. and treated withalcoholic alkali in order to obtain the A1 double bond.

1 methyl 16a,17a-epoxy-A5-pregnen-1,3-diol-2Oonediacetate (IX) reactswith hydrobromic acid to yield the bromohydrin (X), in which the bromineis replaced by hydrogen by hydrogenation of (X), in the presence ofpalladium on charcoal and in the presence of an alkaline reagent, suchas ti'ietliylamine, ammonium acetate or calcium carbonate, to product(XI).

The product (XI) is acylated in the 17-position in the presence oftoluene-p-sulphonic acid to give triacyl compound (XII) which isselectively saponitied .in .the 3- position, for example with KHCO3, toobtain (XIII) which, dissolved in an appropriate solvent such asacetone, is oxidised at a temperature between 15 and +20" C. with anaqueous solution of a mixture of chromic and sulphuric acids, to -give(XIV). Alkali treatment of (XIV) causes the `displacement of the doublebond from position 5 to position 4, the elimination of the acetoxy groupin position 1 with formation of a double bond in posi-tion 1 and, at thesame time, the saponification of the acyloxy group in the 17-position,to yield 1- methyl-l7a-hydroxy-1,Z-dehydroprogesterone (XV).

The acid treatment of (XIV) eliminates the 1-acetoxy group withformation of a double bond in the l-position, and also causes migrationof the double bond in the 5- position to the 4-position. There is thusobtained 1- methyl- 17a acyloxy 1,2 dehydroprogesterone (XVI). Theproduct (XVI) can also be obtained by esteriica- Ytion of the hydroxylgroup in the 17a position of (XV), ffor example by treating it with aderivative of an acid ROH, such as an anhydride or a chloride, in thepresence of toluene-p-sulphonic acid.

Selective acetylation, with acetic anhydride and acetic acid undersuitable conditions, tis effected on A5-pregnen- 1,8,3,20triol (XVIII),prepared by reduction of A5- pregnen-1,8,3/3-diol-20-one-1 diacetate(XVII) with LiAlH4 in a suitable solvent such as tetrahydrofuran orether, to obtain the 3,20-diacetate (XIX). The product (XVII) [which isprepared from ruscogenin (Ia) or from neoruscogenin (Ib) by acetylationof the hydroxyl groups situated in land 3-positions, degradation of thediacetate and hydrogenation with palladium on charcoal] is known (H.Lapin, Bull. Soc. Chim. 1501 (l957)].

The compound (XIX), dissolved in an appropriate solvent such as acetone,is oxidised at a temperature between 15 and +20 C. with an aqueoussolution of a mixture of chromic and sulphuric acids to obtain A5-pregnen-3,B,20diol1-one-3,20diacetate (XX) which is treated with aGrignard reagent, such as CH3MgI or CHsMgBr, in a suitable solvent andsubsequently decomposed, with an acid or a solution of NH4C1, to yield1-niethylA5-pregnenl,3,20triol (XXI). By selective oxidation lin theZO-position of (XXI), `dissolved in an appropriate solvent such asacetone, with an aqueous solution of a mixture of chromic and sulphuricacids and at a temperature between 15 and +20 C., there may be obtainedl-methylA5pregnen1,3-diol-20-one (XXII) which is ,further oxidised inthe 3-position under the same conditions to give`1-methyl-A5-pregnen-1-ol3,20- dione (XXIII), which may be prepared in asingle step by oxidation of (XXI) under the above conditions. Theproduct (XXIII) is rearranged to give l-methyl-l-hydroxy-progesterone(XXIV).

On hydrogenation of the 1monoacetate of 1methylA516-pregnadiene-1,3-diol-20-one (VI) in the presence of a catalyst suchas palladium on charcoal, there is obtained the corresponding pregnene(XXV) which, dissolved in a suitable solvent such as acetone, isoxidised between 15J and +20" C. by an aqueous solution of a mixture ofsulphuric acid and chromic acid to givel-mcthyl-lacetoxy-3,ZO-dioxo-pregn-S-ene (XXVI).

Treatment in acid medium of (XXVI) produces the migration of the doublebond from the 5-position to the 4-position to give 1 methyl 1 -acetoxyprogesterone (XXVII).

Treatment in alkaline medium of (XXVI) produces the migration of thedouble hond from the S-position to the 4-position and the elimination ofthe acetoxy group in the 1-position with formation of the double bond inthe 1position to give l-methyl-1,2-dehydro-progesterone (XXVIII),

9 which can also be prepared from (XXIII) or (XXIV) or (XXVII).

1-Methyl-1hydroxydiosgenin (Va) andl-rnethyl-l-hydoxy-A25(27)-dehydrodiosgenin (Vb) can be selectivelyacetylated in the 3-position to give the corresponding acetates (XXIXaand XXIXb respectively). Dehydration, for example by means of thionylchloride, of the acetates gives essentially the 3-acetate ofl-methylene-diosgenin (XXXa) and the 3acetate of 1methyleneA25 27dehydrodiosgenin (XXXb) which, on catalytic hydrogenation, such as withpalladium on charcoal, give the corresponding 1-methyl derivatives(XXXIa and XXXIC), By degradation of these latter compounds, there isobtained l-methyl-B- hydroxy-A516-pregnadien-20-one (XXXII), of whichthe double bond in the 16-position is selectively hydrogenated in thepresence `of a suitable catalyst such as palladium on charcoal. There isthus obtained 1-methyl-3-hydroxy- A5-pregnen-20-one (XXXIII), which,dissolved in an appropriate solvent such as acetone, is oxidised at atemperature between and +20 C. with an aqueous solution of a mixture ofchromic and surphuric acids, to give 1methylA5pregnen3,2O-diene (XXXIV).1- Methyl-progesterone (XXXV) is prepared from (XXXIV) by causingmigration of the double bond from the 5-position to the 4-position bymeans of an acid or alkaline medium.

Saponication of (XXXa) and (XXXb) gives the corresponding 3-hydroxyderivatives (XXXVIa, XXXVIb) which, on hydrogenation in the presence ofa catalyst such as palladium, gives l-methyl-diosgenin (XXXVIIu) and1-methyl-yamogenin (XXXVIIC), respectively.

The preparation of l-methyl-17otacetoxyprogesterone (XLVII) from the3-acetate of 1-methyleneA25(27)-de hydrodiosgenin (XXXb) may be eiectedas follows. Degradation of (XXXb) gives l-methylene-3-acetoxy-A5116-pregnadien-2O-one (XXXVIII) which is dissolved in a suitablesolvent such as methanol and epoxidised in the 16,17-position, bytreatment with hydrogen peroxide under strongly alkaline conditions, togive 1rnethylene3ace toxy-16a,17a-epoxy-A5-pregnen-20-one (XXXIX).Acetylation of (XXXIX) forms the corresponding 3-acetoxy compound (XL)and treatment of the latter in solution in peroxide-free dioxan with aniodine-free solution of hydriodic acid under oxygen-free conditionscauses rupture of the epoxy ring giving l-methylene-S-acetoxy-16-iodo-17a-hydroxy-A5-pregnen-20-one (XLI). Reduction of (XLI) with Raneynickel and ethanol eliminates the 16,8- iodine atom to give1-methylene-31S-acetoxy-17a-hydroxy- A5-pregnen-2O-one (XLII) andacetylation of this compound gives the corresponding 17a-acetoxycompound (XLIII). Hydrogenation of (XLIII) in the presence of Adamsplatinum saturates the 1-methylene group to give1-methy1-3,17a-diacetoxy-A-pregnen-ZO-one (XLIV) and by selectivesaponication of the latter in the 3-position with HC1 and methanol thereis obtained l-methyl-3- hydroxy-17x-acetoxy-A5-pregnen-20-one (XLV).Oxidation of (XLV) with a solution prepared as described in procedureA(ii) which follows gives 1-methyl-17a-acetoxy- A5-pregnen-3,20dione(XLVI) and heating this in acid medium elIects transposition of the A5double bond to the 4position thus giving 1methyll7acetoxyprogesterone(XLVII).

The examples set forth below will serve to illustrate the production ofcompounds according to the invention. The temperatures are given indegrees centrigrade. The following procedures are illustrative of theproduction of intermediate compounds:

(A) l-KETO-DIOSGENIN (IIa) FROM RUSCOGENIN (In) (i) 40 grams ofruscogenin dissolved in 400 m1. of pyridine are added to a suspension ofCrOa-pyridine cornplex in pyridine (prepared from 40 g. of CrO3 and 400Inl. of pyridine) with stirring and at room temperature. After 20 hoursof stirring the mixture is poured into 3.2 l. of

'10 water. The product is extracted with benzene, the organic extractsare washed with water, dried and evaporated to dryness under vacuum. Theresidue is crystallised from ethyl acetate. Yield: 12.75 g. ofl-keto-diosgenin (Ila) melting at 220-222.

(ii) 14 milliltres of an oxidising solution (prepared from 266 g. ofCrO3, 230 ml. of conc. H2804, 400 m1. of water and the resultingsolution diluted with water to 1 litre) are added to a solution of 20 g.of ruscogenin in 2400 ml. of acetone with stirring at -15. After 1.5minutes, 20 ml. of a 30% aqueous solution of NaI-1803 are added andafter 10 minutes stirring a solution of sodium acetate (13 g. of sodiumacetate BH2C and 30 ml. of Water) is introduced. The mixture isconcentrated to 400 ml. under vacuum and slowly poured into 2 l. ofwater. The precipitate is filtered, washed with Water, dried andcrystallised from acetone. Yield: 10.16 g. of (IIa) melting at 218-224.

(B) RUSCOGENIN-3-ACETATE (Illa) FROM RUSCOGENIN (Ia) A mixture of 140 g.'of ruscogenin, 3360 ml. of acetic acid and 560 g. of acetic anhydrideis heated for 18 hours at 60. The solution is evaporated to dryness invacuo. The crystalline residue is washed with 1 litre of ether, in whichthe 3-acetate of ruscogenin is scarcely soluble. After filtration,washing with ether and drying of the insoluble matter, there areobtained 49 g. of the rst fracc tion, melting point 228-231".

The residue obtained by evaporation of the washing ether of the firstfraction is agitated for 1 hour with 460 ml. of boiling di-isopropylether. The suspension is ltered While hot and the insoluble matter iswashed with ml. of di-isopropyl ether.

After drying, there are recovered 17.5 g. of the second fraction,instantaneous melting point 229-231".

Saponiication with alcoholic potassium hydroxide of the residue ofevaporation of the diisopropyl ether which has been employed to purifythe second fraction permits of recovering 67 g. of ruscogenin, meltingpoint 198-202.

(C) NEORUSCOGENIN-3-ACETATE (IIIb) FROM NEORUSCOGENIN (Ib) By proceedingas in the case of ruscogenin, g. of

neoruscogenin give:

Neoruscogenin-3-acetate, rst fraction: 57 g., melting pointNeoruscogenin-S-acetate, second fraction, recrystallised fromisopropanol: 11.4 g., melting point 24U-245.

Saponicationby means of alcoholic potassium hydroxide of the residue ofevaporation of the mother liquors of the second fraction permits ofrecovering 75 g. of neoruscogenin, melting point 192-200.

(D) 1-KETO-DIOSGENlN-B-ACETATE (IVa) FROM (IIa) A mixture of 12.75 g. of(IIa), 51 ml. of pyridine and 19 m1. of acetic anhydride is shakenover-night at room temperature. The solution is then warmed on awaterbath for 15 minutes and poured into 500 m1. of water` Theprecipitate is filtered, washed with water and dried. Yield: 14 g. ofthe acetate (IVa) melting at 192-194".

(E) 1-KETo-D1OSGEN1N-3-ACETATE (Iva) FROM (ma) 34 g. ofruscogenin-Sacetate dissolved in 4590 ml. of acetone are treated with20.4 ml. of the oxidising solution prepared in procedure A(ii) at 13-15with agitation in a nitrogen atmosphere. The solution is agitated for 4minutes, whereafter 4590 ml. of water are added thereto. After agitationfor 1 hour at 0, the precipitate is ltered, Washed with 50% acetone anddried. There are obtained 32.2 g. of l-keto-diosgenin-3-acetate meltingat 192-194".

l l (F) 1-KETO-A25(27)-DEHYDRODIOSGENIN-3- ACETATE (IVb) FROM (Ilib) 25g. of neoruscogenin-3-acetate dissolved in 3375 ml. of acetone aretreated with 15 ml. of the oxidising solution prepared in procedureA(ii) at 15 with agitation in a nitrogen atmosphere. The solution isagitated for 4 minutes, whereafter 3375 ml. of water are added thereto.After agitation for a quarter of an hour, the precipitate is filtered,washed with 50% acetone and dried. There are obtained 22.3 g. of1-keto-A25 27)-dehy drodiosgenin-3-acetate, Ml. 22S-232.

Example 1 LMETHYL-l-HYDROXY-DIOSGENIN (Va) FROM (IIa) 16.96 grams ofl-keto-diosgenin dissolved in 400 ml. of anhydrous benzene are added toa solution of methylmagnesium iodide in ether (prepared from 40 g. ofMg, 130 g. of CH3I and 760 ml. of anhydrous ether). The suspension iswarmed at 45 47 for 7 days and then slowly poured into an aqueoussolution of NHiCl in water (360 g. of NH4C1 in 1900 ml. of iced water).The organic layer is separated and the aqueous solution is extractedwith ether again. The combined organic extracts are washed with water,dried and evaporated to dryness. The residue is dissolved in 150 ml. ofbenzene and chromatographed on 400 g. of Florisil. 1 methyl-1-hydroxy-diosgenin is eluted with a benzene-ether mixture (1:1). 13.4grams of (Va) melting at 200 are obtained.

Example 2 l-rmTHYL-l-HYDROXY-DIOSGENIN (Va) FROM (Iva) To a solution ofCHBMgl (prepared from 2.9 g. of Mg and 17 g. of CH3I) in 255 ml. ofanhydrous ether is slowly added with gentle boiling a solution of 9.5 g.of (IVa) in 500 rnl. of tetrahydrofuran. This addition takes about 1hour. Ether is distilled olf and, during the distillation,tetrahydrofuran is added until the internal temperature rises to 63. Atthis point the distillation is interrupted and the mixture is boiled for15 hours. The suspension is treated with 400 ml. of a 25% aqueoussolution of NHQCI and, by operating in the usual manner, 5.1 g. of crudel-methyl-l-hydroxy-diosgenin melting at 195-205o is obtained. Aftercrystallisation from aqueous methanol there is obtained 4.35 g. of purel-methyl-lhydroxy diosgenin (Va) melting at 21S-216.

Example 3 LMETHYL-1HYDROXYAW27 -DEHYDRODIOSGENIN (vv) FROM (tvb) To asolution of methyl magnesium iodide (prepared from 3.86 g. of magnesiumand 24.85 g. of methyl iodide in 266 m1. of anhydrous ether) there isadded slowly a solution of 10 g. of 1diete-A25(27)-dehydrodiosgenin-3-acetate (lVb) in 350 ml. of anhydrous benzene. The mixture is refluxedfor 3 hours, shaken for a further 15 hours at room temperature and thentreated with 500 ml. of a 25 aqueous solution of ammonium chloride.

After the usual treatment, the crude product dissolved in benzene ischromatographed on 95 g. of Woelm neutral alumina (activity: l). A smallketone fraction is eluted by 380 ml. of benzene and then the column iseluted by 950 ml. of ethanol. The alcoholic eluate is evaporated todryness under vacuum and the residue is recrystallised from a solutionof methanol in diisopropyl ether. There is obtained 3.55 g. of1-methyll-hydroxy-A25(27)dehydrodiosgenin (Vb), melting at 168- 176".The pure product, obtained by crystallisation from ethyl acetate, meltsat 192-194.

Example 4 l-METHYL-AS,w-PREGNADIEN-l,3,8-DIoL-2oONE-1 ACETATE (VI) FROM(Va) A mixture of g. of 1rnethyl1hydroxydiosgenin (Va), 4.5 g. ofmonomethylamine hydrochloride, 12 ml.

l2 of pyridine and 44 ml. of acetic anhydride is boiled for 2.5 hours.The solution is poured into iced water and extracted with ether after 2hours. The organic extract is washed with 10% HC1, water, 5% NaHCO3 andagain with water. The ether solution is evaporated to dryness. Yield: 18g. of thick oil.

The above oil, dissolved in 300 ml. of acetic acid, is treated with anoxidising solution (9 g. of CrO3, 15 ml. of water and 60 ml. of aceticacid) at 20 with stirring. The stirring is continuned for 75 minutesthan 150 ml. of ethanol are added and the solution is again shaken for 1hour. The solution is concentrated to a small volume, dissolved in 150ml. of ethanol and poured into 300 ml. of water. The suspension isextracted with ether. The extract is concentrated, after being washed toneutrality, and 16.8 g. of oily product are obtained. The 16.8 g. of thelatter product, dissolved in 450 ml. of t-butanol, are allowed to reactwith 27 g. of KOH dissolved in 36 ml. of water at room temperature for16 hours with stirring. The solution is extracted with ether. Afterevaporation of the ether, 9.4 g. of (VI) are obtained as an oilyproduct.

Example 5 1-METHYL-Al-PREGNADIEN-l,a-DIOL-aO-ONE-l- ACETATE (V1) FROM(XXIXa) A mixture of 10.3 g. of l-methyl-l-hydroxy-diosgenin- 3-acetate(XXlXa) prepared as in Example 22, 3.43 g. of monomethylarninehydrochloride, 10.3 ml. of anhydrous pyridine and 20.6 ml. of aceticanhydride is heated under reflux for 21/2 hours (temperature of theheating bath: 160). The solution is poured into 1 litre of water andextracted with ether. The organic extract is washed with 4% hydrochloricacid, water, 10% potassium bicarbonate and finally water. After dryingover sodium sulphate, the ether is evaporated to dryness. Yield: 12.2 g.of a thick yellow oil.

This oil is dissolved in m1. of acetic acid and treated at 15 withagitation with a solution of 3.59 g. of CrO3 in 72 ml. of acetic acid.The agitation is continued for 11/2 hours, whereafter 54 ml. of methanolare added. After having been left over-night at room temperature, thesolution is evaporated to dryness in vacuo (2O mm. Hg). The residue istaken up in 100 ml. of ethanol and ml. of water and the suspensionobtained is extracted with isopropyl oxide. The extract is washed withwater and then with 10% potassium bicarbonate and finally with water.After drying over sodium sulphate, the isopropyl oxide is evaporated todryness. The residual yellow amorphous product (10.5 g.) is dissolved in250 ml. of dioxan. The solution is heated under reflux under nitrogenfor 2 hours with a solution of 18 g. of potassium hydroxide in 24 ml. ofwater. After cooling, the dioxan is evaporated in vacuo (20 mm. Hg) andprogressively replaced during the distillation by the same volume ofwater. rThe residual oil is extracted with ether. The organic extract iswashed with 4% hydrochloric acid, water, 10% potassium bicarbonate andfinally water. After drying over sodium sulphate, followed byevaporation of the ether, the oily product obtained is chromatographedon silica gel. Elution of the column by a mixture of benzene and ethylacetate (1:1) gives 1.98 g. of (VI) which, after crystallisation in amixture of benzene and hexane, melts at 186-187.

Example 6 l-METHYL-Al-PREGNADIEN-l,S-DIOL-fzo-oNm-l- ACETATE (VI) FROM(XXIXI') By proceeding as in Example 5, using 20 g. of l-methyl-1hydroxy-A25(27)-dehydrodiosgenin 3 acetate (XXIXb) prepared asdescribed in Example 23, 3.97 g of (Vl) are obtained, M.P.=183185.

Example 7 A solution of 9.4 g. of crude (VI), prepared as described inExample 4 in 150 ml. of methanol is cooled to 8 and treated with l2 ml.of 4 N NaOH and 24 ml. of 33% H2O2. After standing at 4 for 4 hours, 2ml. of acetic acid are added and the solution is poured into 600 ml. of30% aqueous NaCl. The product is extracted with ethyl acetate, theextract is washed with water and evaporated to dryness. 9.5 grams of(VII) are obtained as an oily product.

Example 8 1-MEV1HYL-16a,17a-EPOXY-AE-PREGNElN-l,B-DIOL-ZO- ONE DIACETATE(IX) FROM (VII) 9.5 grams of product (VII) are acetylated with 10 ml. ofacetic anhydride and 25 ml. of pyridine at room ternperature overnight.The solution is poured into iced water and extracted with ethyl acetate.After evaporation of the solvent, the residue (9.7 g.) is treated with25 ml. of methanol. 2.75 grams of crude diacetate (IX) melting at155-l75 are obtained. After crystallisation from methanol, the meltingpoint rises to l73-177. There may be recovered from the mother liquors,by chromatography on Florisil, a second crop of 1.5 g. of product (IX)melting at 174-177".

Example 9 l-METHYL-l6.a,17wEPOXY-AMPREGNADIEN-a,20--DIONE (VIII) FROM(IX) A solution of 0.81 g. of (IX) in 25 ml. of methanol and l g. ofKHCO3 dissolved in 5 ml. of water is boiled for l hour. The solution isneutralised with acetic acid, poured into water and extracted with ethylacetate. The extract, after evaporation of the solvent, yields the crudecompound (VII). This product, dissolved in 30 ml. of acetone, istreated, while stirring at 10", with 0.8 ml. of the oxidising solutionprepared in procedure A(ii). After 15 minutes, aqueous NaHSO3 is addedand the mixture is extracted with CHZClz. After evaporation of thesolvent, the residue, dissolved in 20 ml. of methanol, is treated in anitrogen atmosphere with 0.8 g. of KOH in l ml. of water for minutes atboiling temperature. The solution is neutralised with acetic acid,concentrated to a small volume, poured into water, extracted with ethylacetate; the solvent is evaporated and the residue chromatographed onFlorisil. The fraction eluted with benzene is evaporated to dryness andthe residue, crystallised from acetone-ether mixture, yields 0.4 g. of(VIH) melting at 2082l0 and showing maximum U.V. absorption at 252 ma.

Example 4 millilitres of acetic acid saturated with hydrobromic acid(32%) are dropped into a solution of 2.5 g. of 1- methyl 16,17a epoxy A5pregnen 1,3 diol 20- one diacetate in 12.5 ml. of acetic acid, at Thesolution is stirred for 45 minutes at room temperature and then slowlypoured into 200 ml. of iced Water. The precipitate is filtered, washedwith water to neutrality and dried under vacuum at room temperature. Thebromohydrn (X) is dissolved in 60 ml. of dioxan and hydrogenated at roomtemperature and atmospheric pressure in the presence of 0.75 g. ofpalladium on charcoal and 2.5 ml. of anhydrous triethylamine. When thehydrogenation is over, the catalyst is ltered and the solution isevaporated to dryness. The residue is dissolved in ethyl acetate, thesolution is Washed with water to neutrality and evaported to dryness.The crude (XI) is crystallised from acetone-petroleum ether mixture.Yield: 2 g. of (XI) melting at l70-174".

14 Example 11 A mixture of 2 g. of (XI), 6 ml. of acetic anhydride and50 mg. of toluene-p-sulphonic acid is heated to 100 for l hour. Aftercooling, the mixture is poured into iced water and the steriod isextracted with ethyl acetate. The extract is washed with an aqueous 10%NaHCO3 solution, then with water and then evaporated to dryness. Theresidue is dissolved in 50 ml. of benzene and chromatographed on 50 g.of Florisil (30-60 mesh). The fractions eluted with benzene andbenzene-ether mixture (9:1) are evaporated and the residue iscrystallised from ether. Yield: 0.9 g. of pure (XII, R=Ac) melting at183-185".

Example 12 l-BIEIIHYL-ira-IIYDROXY-l,2-DEHYDRo-PROGESL TERONE (XV) FROM(XII, R"=Ac) A mixture of 0.9 g. of (XII, R=Ac) dissolved in 25 ml. ofmethanol and 0.9 g. of KHCO3 dissolved in 5 m1. of water is boiled for 1hour. The solution is cooled, neutralised with acetic acid, concentratedto a volume of 10 ml., poured into water and the product is extractedwith ethyl acetate. The extract is washed with water and evaporated todryness. The residue (XIII, R"=Ac) is dissolved in 30 m1. of acetone andthe solution is cooled to -10. 0.9 millilitre of the oxidising solutionprepared in procedure A(ii) is added to the prepared solution and thetemperature is kept at 10 for`another 15 minutes. The excess of CrO3 isreduced with a solution of sodium bisulphite, the solution is dilutedwith water and the product extracted with ethyl acetate. The extract iswashed with water and evaporated. The residue (XIV, R"=Ac) is dissolvedin 20 ml. of methanol and mixed with 0.8 g. of KOH dissolved in 1 m1. ofwater and the mixture is boiled for 5 minutes in a nitrogen atmosphere.The solution is neutralised with acetic acid and concentrated undervacuum; ethyl acetate is added and the organic solution is washed withwater and evaporated.

The residue of crude (XV), dissolved in benzene, is chromatographed on12 g. of Florisil (30-60 mesh). The column is eluted with benzenecontaining 10% to 25% ether and the fractions are combined andevaporated. By crystallisation of the residue from acetone-ether oracetone-petroleum ether mixture, 450 mg. of pure (XV), melting at220-224, are obtained. VMaximum U.V. absorption is at 250 mp.

Example 13 To 0.28 g. of crude 1 methyl A5 pregnen 1,17adiol-3,20-dione-diacetate (XIV, R=Ac), dissolved in 25 ml. of ethanol,2.5 ml. of N H2804 are added and the mixture is heated for 5 minutes.`0.5 gram of potassium acetate are added and the solution isconcentrated to 10 ml. under vacuum. Water is added and the precipitateis filtered, washed with water, dried and crystallised from methanol.

milligrams of (XVI, R=Ac), melting at 196- 198, are obtained. MaximumU.V. absorption is at 251 ma (e=l2,400 in 95% ethanol).

Example 14 (a) AS-PREGNE-Nno-TRIOL (XVIII) FROM (XVII) To a suspensionof 52.4 g. of LiAlH4 in 1570 ml. of anhydrous tetrahydrofuran are added,at room temperature, 65.5 g. of A5 pregnen 1,8,3 diol 20 one 1,3diacetate (XVII) (prepared according to Lapin, loc. cit.) dissolved in655 ml. of tetrahydrofuran. After the addition, which takes about 70minutes, the mixture is'boiled for two hours. After the usual treatment,the crude product is crystallised from a methanol-water mixture.

Yield: 37.5 g. of (XVIII) melting at 259-261.

adsense 15 (b) A-PREGNEN-l,B,ZOB-TRIOL-SO-DIACETATE (XIX) FROM (XVIII)To a solution of 68.5 g. of triol (XVIII), dissolved in 822 ml. ofacetic acid, are added 274 ml. of acetic anhydride and the mixture iswarmed at 60 for 3 hours, and then allowed to stand at room temperaturefor 8 days. The solution is evaporated under vacuum and the oilyresidue, dissolved in ether, is washed with aqueous 10% KHCO3 solution,and dried over Na2SO4. After evaporation of the solvent, the residue,dissolved in a benzeneethyl acetate mixture is stirred with aluminumtrioxide for hours, and then the suspension is filtered. The solventsare distilled off under vacuum and the powdery residue is crystallisedfrom methanol. Yield: 43 g. of (XIX) melting at 140-150. Aftercrystallisation from a hexane-ethyl acetate mixture, the melting pointrises to 158- 160 and 26.5 g. of pure (XIX) is obtained.

17.4 millilitres of the oxidising solution prepared in procedure A(ii)are added at +15", with stirring and in a nitrogen atmosphere, to 26.5g. of (XIX) dissolved in 3.57 l. of acetone. The addition takes about 10minutes, and then the stirring is continued for 4 minutes. The mixtureis poured into 17.9 l. of water, and after stirring at room temperatureovernight, the precipitate is filtered and washed with water. The crude(XX) is dried and crystallised from isopropyl ether. Yield: 16.8 g. ofpure (XX) melting at lOl-104.

(d) l-METI-IYL-A-PREGNEN-1,3,20-TRIOL (XXI) FROM .(XX)

To a solution of CH3MgI (prepared from 10.8 g. of Mg and 63 g. of CHBI)in 900 ml. of anhydrous ether are added slowly and with continuousboiling 18.6 g. of (XX) dissolved in 1080 ml. of tetrahydrofuran. Thetime required for this addition is about l hour. Ether is then distilledoff with simultaneous addition of tetrahydrofuran, until the internaltemperature rises to 63. Thereafter, the mixture is boiled for 15 hoursand then decomposed with 1200 ml. of aqueous NH4C1 solution. Afterextraction, evaporation of the solvent and crystallisation of the crudeproduct from ethyl acetate, 10 g. of (XXI) melting at 213-214 areobtained.

Example 15 1 ME'IIIYL-AG-PREGNEN-1,3-DIOL-20ONE (XXII) FROM (XXI) 2.1grams of (XXI), dissolved in 283 ml. of acetone, are treated wlth 3:35ml. of the oxidising solution prepared in procedure A(11) at -l-15 withstirring and in a nitrogen atmosphere. The solution is stirred for afurther 4 minutes and poured into 1400 ml. of water. After standing for2 hours in a refrigerator, the precipitate is filtered, washed withwater and dried. 0.72 gram of (XXII) melting at ISO-185 are obtained.The mother liquors are concentrated and extracted with ether. A secondcrop of (XXII) is obtained (0.28 g. melting at 18S-188).

Example 16 l-METHY-L-AG-PREGNEN-I-OL-3,20DIONE (XXIII) FROM (XXII) 0.72gram of (XXII) dissolved in 97 ml. of acetone are treated as describedin Example 15 with 0.5 ml. of the oxidising solution prepared inprocedure A(ii). 0.41 gram of (XXIII) melting at 188-195 are obtained.After crystallisation from methanol the melting point rises to 202-204.

. Example 17 l-METHYL-l-HYDROXY-PROGESTERONE (XXIV) FROM (XXIII) Amixture of 0.28 g. of (XXIII), 12 ml. of methanol and 1 ml. of N H2SO4is boiled for 1 hour. After cooling, the precipitate obtained isfiltered and dried. Yield: 0.17 g. of (XXIV) melting at 178-182. Aftercrystallisation 1 6 from ethyl acetate the melting point rises to 188.Maximum U.V. absorption is at 244 mp.

Example 18 l-METHYL-l-ACETOXY-a-HYDROXV-2o-OX0-IREGNv -ENE (XXV) FROM(VI) 2.25 grams of 1-methyl-A5-15pregnadien1,3-diol-20- one-l-acetate(VI) prepared in accordance with Example 5 are hydrogenated underatmospheric pressure and at room temperature in 112 ml. of ethyl acetatein the presence of 2.25 g. of 3% palladium on charcoal. After fixationof l mole equivalent of hydrogen, the hydrogenation is stopped. Thecatalyst is filtered and the solution is evaporated to dryness in vacuo.After crystallisation of the residue from isopropyl oxide, 2.02 g. of(XXV) are obtained, M.P.=189-190.

Example 19 LME'II-IYL-l-ACETOXY-3,2o-DIOXOPREGN--ENE (XXVI) FROM (XXV)0.5 gram of (XXV) dissolved in 21 ml. of acetone are treated at 10 undernitrogen with 0.63 ml. of the oxidising solution prepared in procedureA(ii). The agitation is continued at -10 for 15 minutes, whereafter 2.5ml. of methanol are added to the solution, which is poured into ml. ofwater. The precipitate is filtered, Washed with water and dried. 0.41gram of crude (XXVI) is obtained, MI. 170-l74.

Example 20 rMnrr-IYL-I-ACETOXY-PROGEsTERoNE (XXVII) FROM (XXVI) Asolution of 0.5 g. of crude (XXVI) in 39 ml. of methanol, 2.37 ml. of Nsulphuric acid and 7.72 ml. of water is heated under reflux for 1 hour.The methanol is evaporated in vacuo. The oil obtained is extracted withethyl acetate. The organic extract is washed with a 10% aqueous KHCOSsolution and then with water and dried over sodium sulphate. The solventis evaporated on the water bath and the residual oil is chromatographedon silica gel. On elution with benzene containing 25% of ethyl acetate,0.105 g. of pure (XXVII) are obtained, M.P.=136138.

Infra-red spectrum (KBr tablet), bands at: 1726 cm.-1 (ester), 1705cm.-1 C=O in 20-position), 1668 cm.1 C=O in 3-position conjugate), 1612cm.1 (A4).

Ultra-violet spectrum: }\(95% ethanol max.)=245 m/I, e=14,980.

Example 21 I-METHYL-l,2-DEHYDRo-PR0GESTER0NE (XXVIII) FROM (XXVI) Asolution of 1.32 g of. potassium hydroxide pellets in 1.65 ml. of wateris added to a boiling solution of 1.5 g. of (XXVI) in 33 ml. ofmethanol. Heating under reflux is continued for 5 minutes. The solution,cooled to room temperature, is neutralised by 1.44 ml. of acetic acid,whereafter 21 ml. of water are added thereto. The precipitate isfiltered, washed with methanol containing 40% of water and dried. 0:805gram of (XXVIII) is obtained, which, after crystallisation from methanolcontaining 20% of Water, melts at 147-148 and resolidies, and meltsagain at 177-178. [M1320 (c.=l, 95% ethanol)=-32.

Infra-red spectrum (KBr tablet), bands at: 1699 cm.1 C=O in20-position), 1658 emr1 C=O in 3-position conjugate), 1622 cmi1 (A4),1601 cm.-1 (A1).

Ultraviolet spectrum: }\(95% ethanol max.)=252 mp., 6:18850.

Example 22 l-METHYL-l-HYDROXY-DIOSGENIN-S-ACETATE (XXIXa) FROM (Va) Asolution of 4.1 g. of (Va) in 8 ml. of pyridine and 4 ml. of aceticanhydride is heated for 1 hour on a water bath. After cooling, thesolution is poured into ml. of iced water. The precipitate is filtered,washed with water and dried.

4.25 grams of (XXIXa), M.P. 18S-190, are obtained. Afterrecrystallisation from ethanol, the product melts at 197-198".

Example 23 A solution of 4 g. of (Vb) in 36 ml. of pyridine and 24 ml`of acetic anhydride is heated for 1 hour on a water bath. After cooling,the solution is poured into 300 ml. of iced Water. The precipitate isfiltered, washed with water and dried. After recrystallisation fromethanol, 2.185 g. of (XXIXb) are obtained, M.P. Z22-226.

yExample 24 LMETHvLnNE-DroseENIN-s-ACETATE (xxxa) FROM (xxrxa) 6millilitres of thionyl chloride are poured drop-bydrop into a solutionof 10 g. of (XXMa) in 170 ml. of pyridine maintained at The solution isthen agitated for 15 minutes at.0 and then poured into 900 ml. of icedwater. The precipitate is filtered, washed with water, dried andrecrystallised from ethanol and then from isopropanol. 4.37 g. of (XXXa)are obtained, M P. 156.

Example 25 LMETHYLDIOsGE'NIN-s-ACEITATE (xxxramnornxxxa) 2 grams of1-methylene-diosgenin-3-acetate (XXXa) are hydrogenated in 225 ml. ofethanol in the presence of 1.5 g. of palladium on charcoal at roomtemperature and atmospheric pressure. After fixation of 1 moleequivalent of hydrogen, the hydrogenation is stopped. The catalyst isfiltered and the alcoholic liquor distilled to dryness in vacuo.

After repeated recrystallisations of the residue from ethanol, 0.4 g. of(XXXIa) are obtained, M.P. 146-l48, [M1322 (c.=1, CHCl3)=-90.

AExample 26 1-l\IETH;YLENE-A25(27 -DEHYDRODIO S GENIN-3-ACETATE (XXXb)FROM (XXIXb) LMETHYL-YAMO GnNrN-s-ACETATE (xxxrc) FROM (xxxb)v 5.7grains of 1-methylene-A25(27)-dehydrodiosgenin-3 acetate (XXXb) arehydrogenated in 635 ml. of ethanol in the presence of 5.7 g. of 5%palladium on charcoal under atmospheric pressure and at ambienttemperature. After fixation of 2 mole equivalents of hydrogen, thehydrogenation is stopped. The catalyst is filtered and the alcoholicliquor is evaporated to dryness in vacuo.

After crystallisation of the residue from isopropanol, 2.81 g. of(XXXIc) are obtained, M.P.=18l-183, [0:]1322 (c.=1, CHCl3)=-90.

Example 28 l-METHYL-s-HYDROXY-Avl-PREGNADIEN-ao-ONEi (XXXII) FROM(XXXIc) A mixture of 7.13 g. of (XXXIc), 2.38 g. of methylaminehydrochloride, 7.13 ml. of pyridine and 14.26 ml. of acetic anhydride isheated under reflux for 21/2 hours. The solution'is poured into iced`water and extracted with t 18 ether. The ethereal extracts are washedwith N hydrochloric acid, water, a 10% aqueous solution of KHCO3 andnally with water. After drying and evaporation of the ether, 7.3 g. of abrown amorphous product are obtained.

This crude product dissolved in 60 m1. of acetic acid is treated with anoxidising solution (2.56 g. of CrO3 and 51 ml. of 90% acetic acid) at 15with agitation. The agitation is continued for 11/2 hours, 40 ml. ofmethanol are added and the solution is again agitated for 1 hour. Thesolution is distilled to dryness in vacuo, the residue is dissolved inml. of 50% aqueous ethanol and the aqueous alcoholic solution isextracted with diisopropyl ether. The organic extracts are washed withwater and then with a 10% aqueous solution of KHCO3 and finally withwater. After drying and evaporation of the solvent, 7.5 g. of anamorphous product are obtained.

The preceding crude product is dissolved in 182 ml. of dioxan. There isadded to the solution thus obtained a solution of 5.1 g. of potassiumhydroxide tablets in 102 ml. of water and the mixture is heated for 2hours under gentle reflux. After cooling, the dioxan is distilled invacuo and progressively replaced during the distillation by the samevolume of water.v The precipitate which is formed is filtered, washedwith water and dried.

4.3 g. of brown product (XXXII) are obtained which, after purificationby condensation with Girards reagent T, followed by crystallisation fromethanol, give pure (XXXII), Ml. 190-193".

Example 29 1-METHYL-S-HYDROXY-A-PREGNEN-ZO-ONE (XXXIIII) FROM (XXXII)0.35 gram of (XXXII) is hydrogenated at atmospheric pressure and roomtemperature in 30 ml. of ethyl acetate in the presence of 0.35 g. of 5%palladium on charcoal. The theoretical quantity of hydrogen is fixed in35 minutes. The catalyst is filtered, the solution is distilled todryness in vacuo and the residue is recrystallised from ethyl acetate.0.18 gram of (XHIII) are obtained, M.P. 189-l90.

Example 30 1-METHYL-A5-PREGNEN-8,20DIONE (XXXIV) FROM (XXXIII) 8Omilligrams of (XXXIII) dissolved in 10.8 ml. of acetone are treated with0.06 ml. of the oxidising solution prepared in procedure A(ii) at 15with agitation and in a nitrogen atmosphere. The solution is agitatedfor 3 minutes and poured into 54 ml. of water. The precipitate isfiltered, washed with water and dried. 60 milligrams of crude (XXXIV)are obtained, M.P. --177".

Example 31 l-METHYL-PROGESTERONE (XXXV) FROM (XXXIV) 65 milligrams ofcrude (XXXIV) are dissolved in 1.4 ml. of methanol t'o which a drop of10% aqueous potassium hydroxide solution has been added. The solution isheated under reflux for 5 minutes and neutralised with a drop of aceticacid, whereafter 1.4 Inl. of Water is added thereto. The crystallineprecipitate is filtered, washed with water, dried and recrystallisedfrom methanol containing 20% of water. 31 milligrams of XXXV areobtained, M.P.=154156.

Infra-red spectrum (KBr tablet), bands at: 1705 cm.1 C=O in20-position), 1675 cm1 C=O in 3-p0si- `tion conjugate), 1620 cm.-1 (A4).

Ultra-violet spectrum: A (95% ethanol max.)=245m,a, e=13,400.

Example 32 1-METHYLENE-DIOSGENIN (XXXVIa) FROM (XXXa) 8.17 grams of 1methylene diosgenin 3 acetate (XXXa), prepared as described in Example24 are added to a solution of 8.17 g. of potassium hydroxide pellets in817 ml. of methanol; the mixture is heated to reflux for one hour undernitrogen and with agitation. After cooling the solution 8.17 ml. ofacetic acid are added thereto and the mixture is evaporated to drynessunder vacuum; the crystalline residue is taken up in 250 ml. of water,the solution filtered and the residue washed with water and then driedover-night under vacuum in the presence of concentrated sulphuric acid.

The crude product is dissolved in 134 ml. of benzene and thenchromatographed on a column of silica gel (134 g.). Elution of thecolumn with a benzene ethyl acetate mixture (95:5) leads to theisolation of 5.09 g. of l-methylene-diosgenin, M.P. 148 -149, [a]D20=-91i (c.=1, chloroform).

Example 33 1-METHYLENRAM 21 DnHYDRoD1oSGENIN (xxxvrb) FROM (xxxb)Example 34 1-METHYL-DIOSGENIN (XXXVIIa) FROM (XXXvIa) 1.33 grams ofl-methylene-diosgenin (XXXVIa) dissolved in 66 ml. of ethanol arehydrogenated in the presence of 2.66 g. of 3% palladium on charcoalunder atmospheric pressure and at room temperature. The hydrogenation isstopped after the absorption of 1.4 mole equivalents of hydrogen; thecatalyst is then filtered off and the ethanolic solution evaporated todryness under vacuum.

The crude product is dissolved in 50 ml. of benzene and thenchromatographed on a column of silica get (25 g.). Elution of the columnwith a benzene-ethyl acetate mixture (9:1) gives 0.63 ofl-methyl-diosgenin, M.P. 125- 130'.

Example 35 l-METHYL-YAMOGENIN (XXXVIIC) FROM (XXXVIII) 2 grams of 1methylene A25(27) dehydrodiosgenin (XXXVIIJ) dissolved in 100 ml. ofethyl acetate are hydrogenated in the presence of 1.6 g. of 10%palladium on barium sulphate under atmospheric pressure and at roomtemperature. The hydrogenation is stopped after the absorption of 2.3mole equivalents of hydrogen; the catalyst is then filtered off and thefiltrate evaporated to dryness under vacuum.

The crude product is purified by two crystallisations from ethanol andthere is obtained 0.32 g. of 1-methylyamogenin, M.P. 177-178.

Example 36 LME'IHY-LDIO S GENIN ACETATE (XXXIa) FROM (XXXa) 6.9 grams of1-methylene-diosgenin acetate (XXXa) are hydrogenated in a mixture of414 cc. ethyl acetate and 13.8 cc. acetic acid in the presence of 0.69g. of Adams platinum at ordinary pressure and temperature; theabsorption of hydrogen is very rapid and when it falls to about 2 cc. ofhydrogen per minute the hydrogenation is stopped, the volume of hydrogenabsorbed then corresponding to about 1.1 molecular equivalents. Theduration of the hydrogenation is 45 minutes- The catalyst is filteredoff and the filtrate evaporated to dryness under Vacuum. Afterrecrystallisation of the residue from 63 cc. of ethanol there isobtained 4.49 g. of (XXXIa), melting point 147-149, [a]D26=-92i2 (c.= 1,chloroform).

2O Example 37 1-METHYLENE-S-ACETOXY-AGJU-PREGNADIEN-ZO-ONE (XXXVIII)FROM (XXXb) A mixture of 77.2 g. of crudey1-methylene-A25(2W-dehydrodiosgenin acetate (prepared as described inExample 26), 25.7 g. of monomethylaminehydrochloride, 77.2 cc. ofanhydrous pyridine and 144.4 cc. of acetic anhydride is heated at thereflux for 21/2 hours (at a temperature of 144). The solution is pouredinto 2,300 cc. of water and extracted with ether. The organic extract iswashed successively with 4% hydrochloric acid, water, with a saturatedaqueous solution of sodium bicarbonate and finally with water. Afterdrying over sodium sulphate, the ether is evaporated to dryness. Yield:85.5 g. of a red-brown oil.

This oil is dissolved in 662 cc. of acetic acid and treated at 15 withagitation with a solution of 28 g. chromic oxide in 563 cc. of aqueousacetic acid; the agitation is continued for 11/2 hours and then 402 cc.of methanol are added. After being left over night at ambienttemperature the solution is evaporated to dryness under vacuum (20 mm.Hg); the residue is taken up into a mixture of 565 cc. of ethanol and503 cc. of water and the suspension obtained extracted into diisopropylether. The extract is washed successively With Water, with an aqueoussolution of 10% potassium bicarbonate and finally with water; afterdrying the extract over sodium sulphate, the diisopropyl ether isevaporated to dryness. Yield: 81 g. of a yellow oil.

This oil is dissolved in 810 cc. of acetic acid; the solution obtainedis heated at the reflux for two hours and after cooling, the acetic acidis evaporated to dryness under vacuum (20 mm. Hg). The oily residue isdissolved in l litre of ethyl acetate; the organic solution is washedsuccessively with water, with an aqueous solution of 10% potassiumbicarbonate and finally with water and, after drying over sodiumsulphate and evaporation of the ethyl acetate under vacuum, the crudeproduct obtained is chromatographed on silicon gel. Elution of thecolumn with benzene containing 2% ethyl acetate gives l30.7 g. of(XXXVIII), melting at 138-140.

Example 38 l-nmTHYLENE-a-HYDROXY-lcalm-EPOXY-A- PREGNEfN-ZO-ONE (XXXIX)FROM (XXXVIII) A solution of 30.7 g. of (XXXVIII) in 3.07 litres ofmethanol is treated with 62.5 cc. of 4 N sodium hydroxide and cc. of 33%hydrogen peroxide; the solution is left to stand for 17 hours at about4, then filtered to remove a small quantity of insoluble material, andpoured into 3.1 litres of Water. The resulting crystalline suspension isleft to stand for 4 hours at about +4 and then filtered; 24.9 g. of(XXXIX) are obtained, melting point 141- 142.

Example 39 1-METHYLENE-l-ACETOXY-l 6a,17a-EPOXYA5 PREGNEN-20-ONE (XL)FROM (XXXIX) 24.9 grams of (XXXIX) are acetylated with 24.9 cc. ofacetic anhydride in 49.8 cc. of anhydrous pyridine by heating at 100 for1% hours. The solution is decolorised with 1.5 g. of carbon black,cooled to the ambient temperature and poured into 75'0 cc. of Water; theacetyl derivative precipitates and after filtration 27.5 g. of (XL) areobtained, melting at -132.

Example 40 l-METHYLENE-s-ACETOXY-le-IoDo-lra-HYDROXY-AU- PREGNEN-zo-ONE(XLI) FROM (XL) 100 cc. of a 57% aqueous solution of hydriodic acid,previously freed from all traces of iodine by agitation for severalminutes with 0.5 g. of copper powder, are added all at once to asolution of 10 g. of (XL) in 500 cc. of peroxide-free dioxan and intothis mixture is bubbled a light current of nitrogen. 20 minutes afterthe yaddition of the hydriodic acid, 1.5 litres of distilled Water areadded to the solution and the suspension obtained is extracted withperoxide-free diethyl ether, the operation being conducted undernitrogen. The ethereal extract is Washed with Water, dried over sodiumsulphate and evaporated to dryness; 17 g. of (XLI) are obtained in theform of a brown oil, which may be used directly in the procedure of thefollowing example.

Example 41 1METHYLENE-s-ACETOXY17a-HYDR0XY-A5-PREGNEN- adorna-(XLII)FROM(XLI) 55 grams of Raney nickel are added to a solution of 17 g. of(XLI) dissolved in 600 cc. of ethanol; the suspension obtained isagitated at ambient temperature in darkness yand under nitrogen for 30minutes. After filtering off the nickel, the ethanol is distilled olf todryness under vacuum (20 mm. Hg) and the residue is crystallised from amixture of 8 cc. of diethyl ether and 16 cc. of hexane. After filtration7.77 g. of (XLII) are obtained, melting at 154- 155.

Example 42 l-METHYLENE3/3,17a-DIACETOXY-AS-PREGNEN20-ONE (XLIII) FROM(XLII) A mixture of 2,95 g. of (XLII), 44 cc. of acetic anhydride and0.59 g. of toluene-p-sulphonic acid is agitated under nitrogen atambient temperature for 16 hours. The solution is then poured into 200cc. of iced Water and the steroid which precipitates is filtered olf,washed with water, and dried; 3.08 g. of (XLIII) are obtained, meltingat 183 184. After recrystallisation from an ethyl acetatehexane mixture(1:3), the pure product melts at 184- 185", [a]D24=-30l 1 (c.=1,chloroform).

Example 43 1-METHYL-3,l7a-DIACETOXY-A5-PREGNEN20-ONE (XLIV) FROM`(XLIII) 1 gram of (XLIII) is hydrogenated at ordinary pressure andtemperature in a mixture of 60 cc. of ethyl acetate and 4 cc. cf aceticacid in the presence of 0.2 g. of Adams platinum. The absorption ofhydrogen is rapid and when it has fallen to about 0.2 cc. of hydrogenper minute, the hydrogenation is stopped; the volume of hydrogenabsorbed then corresponds to about 1.1 molecular equivalents. Theduration of the hydrogenation is 25 minutes.

The catalyst is ltered off and the filtrate evaporated under vacuum todryness; after washing the crystalline residue 4 times with 1.5 cc. ofhexane, 0.89 g. of (XLIV) are obtained, melting at 157-159; [a]D24=-50i2(c.=1, chloroform).

Example 44 A mixture of 1.57 g. of (XLIV) in 47 cc. of methanol and 0.32cc. of concentrated hydrochloric acid (d.=1.19) is heated under reux for1f1/2 hours. A solution of 0.38 g. of potassium bicarbonate in 47 cc. ofwater is added to the boiling solution. On cooling to ambienttemperature the steroid crystallises and after filtration and drying1.19 g. of (XLV) are obtained, melting at 197 l99; [oL]D23 =60i1 (c.=1,chloroform).

Example 45 1.12 cc. of the oxidising solution prepared as describedabove in procedure A(ii) are added under nitrogen and with agitation toa solution of 1.166 g. of (XLV) in 1517 cc. of acetone and Whilemaintaining the temperature of the medium at about The agitation iscontinued for 5 minutes and the suspension is then diluted with 200 cc.of Water which initiates crystallisation of the steroid. After leavingthe suspension to stand at about 4 for two 22 hours, the steroid isltered off, Washed with an acetone- Water mixture (1:1) and dried. 0.96g. of (XLVI) are obtained, melting at 202-204.

Example 46 1METHYLl7a-ACETOXYPROGESTERONE (XLVII) FROM (XLVI) A mixtureof 0.96 g. of (XLVI), 76 cc. of methanol, 4.6 cc. of N sulphuric acidand 15.3 cc. of Water is heated under reflux for 1 hour. A solution of1.2 g. of sodium acetate in 76 cc. of Water is then added to the boilingsolution and on cooling to ambient temperature the steroid crystallises.After filtration and drying, 0.82 g. of (XLVII) are obtained, melting at207.

The pure product obtained on recrystallisation from methanol melts at2l42l5, it resolidilies and remelts at 226-227; [a]D25.=+81i1 (c.=1,chloroform); U.V. spectrum: )t 95% ethanol max.=244 ma; e=15,190.

This application is a continuation-impart of application Serial No.64,4612, filed October 24, 1960, noW abandoned.

We claim:

2. A process for the preparation of l-methyl-l-acetoxy-B-hydroxy-Afl16-pregnadien-20-one which comprises reacting a compoundselected from the class consisting of l-methyl-l-hydroxy-diosgenin andthe 3-acetate thereof and 1-methyl-1-hydroxy-A25(27)-dehydrodiosgeninand the 3-acetate thereof With acetic anhydride in the presence of areagent selected from the class consisting of pyridine and apyridine-monomethylamine hydrochloride mixture, oxidising the triacetylderivative obtained with a chromic acid-acetic acid mixture andsaponifying the resultant compound with an alkali metal hydroxide.

3. A process for the preparation of a 1-methyl-3-keto A1A-steroid of thepregnane series which comprises oxidising in the 3position alamethyl-l-acetoxy-3-hydroxysteroid of the pregnane series with areagent selected from the class consisting of an aqueous solution of achrornic acid-sulphuric acid mixture and a pyridine-chrornic anhydridecomplex and reacting the product obtained with a reagent selected fromthe class consisting of alkali metal hydroxides and strong mineralacids.

4. A process for the preparation of a 1methyl1,3dihydroxy-ZO-keto-steroid of the pregnane series which comprisesreacting a compound selected from the class consisting of1,3,B-dihydroxy-20-keto-steroids of the pregnane series and thel-diacetates thereof with lithium aluminum hydride, acetylating in the 3and 20- positions the 1,3,20-trihydroxysteroid thus obtained with aceticanhydride, oxidising in the 1-position the resultant3,20-diacetoxysteroid with a reagent selected from the class consistingof a chromic acid-sulphuric acid mixture and a pyridine-chromicanhydride complex, reacting the 1-oxo-3[3,120-diacetoxy-steroid thusformed with a methyl magnesium halide, hydrolysing the magnesium complexof the 1-methyl-3,20diacetoxysteroid so obtained in a weakly acidicmedium and oxidising in the 20-position the resultantl-methyl-1,3,20trihydroxysteroid with a reagent selected from the classconsisting of a chromic acid-sulphuric acid mixture and apyridine-chromic anhydride complex.

References Cited in the file of this patent UNITED STATES PATENTS2,686,181 Julian et al Aug. 10, 1954 2,837,464 Nobile June 3, 19582,962,510 Hiersemann et al Nov. 29, 1960 2,971,886 Babcock Feb. 14, 1961OTHER REFERENCES Djerassi et al.: J. Amer. Chemistry Soc., vol. 78(1956), pages 2479-2481 relied on.

Burn et al.: J. Chem. Soc., vol. 80 (1958), pages 795- 799 relied on.

2. A PROCESS FOR THE PREPARATION OF1-METHYL-1-ACETOXY3B-HYDROXY-$5,16-PREGNADIEN-20-ONE WHICH COMPRISESREACTING A COMPOUND SELECTED FROM THE CLASS CONSISTING OF1-METHYL-1-HYDROXY-DIOSGENIN AND THE 3-ACETATE THEREOF AND1-METHYL-1-HYDROXY-$25(27)-DEHYDRODIOSGENIN AND THE 3-ACETATE THEREOFWITH ACETIC ANHYDRIDE IN THE PRESENCE OF A REAGENT SELECTED FROM THECLASS CONSISTING OF PYRIDINE AND A PYRIDINE-MONOMETHYLAMINEHYDROCHLORIDE MIXTURE, OXIDISING THE TRIACETYL DERIVATIVES OBTAINED WITHA CHROMIC ACID-ACETIC ACID MIXTURE AND SAPONIFYING THE RESULTANTCOMPOUND WITH AN ALKALI METAL HYDROXIDE.